Advanced biliary tract cancer(BTC)and pancreatic ductal adenocarcinoma(PDAC)have poor prognoses and limited treatment options.Here,we conducted thisfirst-in-class phase II study to evaluate the efficacy and safety of ...Advanced biliary tract cancer(BTC)and pancreatic ductal adenocarcinoma(PDAC)have poor prognoses and limited treatment options.Here,we conducted thisfirst-in-class phase II study to evaluate the efficacy and safety of SHR-1701,a bifunctional fusion protein targeting programmed death-ligand 1(PD-L1)and transforming growth factor-beta(TGF-β),combined with famitinib,a multi-targeted receptor tyrosine kinase inhibitor,in patients with advanced BTC or PDAC who failed previous standard treatment(trial registration:ChiCTR2000037927).Among 51 enrolled patients,the BTC cohort showed an objective response rate(ORR)of 28%(including 2 complete responses)and a disease control rate(DCR)of 80%,with a median progression-free survival(mPFS)of 5.1 months and a median overall survival(mOS)of 16.0 months.In the PDAC cohort,the ORR was 15%(2 complete responses),with a DCR of 60%,and the mPFS and mOS were 2.1 months and 5.3 months,respectively.Grade 3 or 4 treatment-related adverse events(TRAEs)occurred in 29.4%of patients,with no grade 5 TRAEs reported.Exploratory analyses revealed that primary tumor resection history,peripheral blood immunophenotype changes,and distinct immune-metabolic profiles were associated with treatment benefits.An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts,allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen.In conclusion,our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC,highlighting the promise of targeting PDL1,TGF-β,and angiogenesis pathways simultaneously.展开更多
This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxal...This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment forunresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologicallyconfirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients receivedSHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m^(2)) intravenously on day 1, along with oral capecitabine(1 g/m^(2) twice daily) on days 1-14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenancetherapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) perRECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival(PFS) was 10.3 months (95% CI: 8.3-13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% ofpatients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that hightumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactatedehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safetyprofile and potent antitumor activity in unresectable mCRC.展开更多
The randomized phase 3 CHART trial(NCT03520478)revealed that rezvilutamide(REZ)plus androgen deprivation therapy(ADT)in high-volume,metastatic,hormone-sensitive prostate cancer(mHSPC)significantly enhanced radiographi...The randomized phase 3 CHART trial(NCT03520478)revealed that rezvilutamide(REZ)plus androgen deprivation therapy(ADT)in high-volume,metastatic,hormone-sensitive prostate cancer(mHSPC)significantly enhanced radiographic progression-free and overall survival than bicalutamide(BIC)-ADT.Accordingly,we examined patient-reported outcomes(PROs)results,which were exploratory endpoints in the CHART trial.The patients were randomly allocated to receive REZ-ADT or BIC-ADT in a 1:1 ratio.The PROs were evaluated with the Brief Pain Inventory-Short Form(BPI-SF)and the Functional Assessment of Cancer Therapy-Prostate(FACT-P)questionnaires.Both study groups displayed comparable baseline pain scores and functional status.Patients administered REZ-ADT had an extended time to progression of worst pain intensity in comparison to those treated with BIC-ADT(25th percentile,9.2[95%CI 7.4-16.6]vs.6.4 months[95%CI 5.5-8.3];HR 0.75[95%CI 0.57-0.97];p=0.026).Similarly,patients received REZ-ADT exhibited a delayed time to progression of pain interference in comparison to those receiving BIC-ADT(25th percentile,20.2[95%CI 12.9-31.3]vs.10.2 months[95%CI 7.4-11.1];HR 0.70[95%CI 0.52-0.93];p=0.015).Additionally,the REZ-ADT group demonstrated a prolonged delay in the deterioration of the total score on the FACT-P questionnaire(25th percentile,12.8[95%CI 7.4-20.3]vs.6.0 months[95%CI 4.6-9.2];HR 0.66[95%CI 0.50-0.86];p=0.002),as well as most of the FACT-P subscale scores,in comparison to the BIC-ADT group.In conclusion,REZ-ADT is superior to BIC-ADT regarding the pain alleviation and enhancement of functional scales for high-volume mHSPC.展开更多
Background:Although programmed cell death 1(PD-1)blockade plus chemotherapy can significantly prolong the progression-free survival(PFS)and overall survival(OS)in first-line settings in patients with driver-negative a...Background:Although programmed cell death 1(PD-1)blockade plus chemotherapy can significantly prolong the progression-free survival(PFS)and overall survival(OS)in first-line settings in patients with driver-negative advanced non-small-cell lung cancer(NSCLC),the predictive biomarkers remain undetermined.Here,we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD-1 blockade plus chemotherapy.Methods:Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone.Tumor immune microenvironmental markers,including PD-1 ligand(PDL1),CD8,CD68,CD4 and forkhead box P3,were assessed using multiplex immunofluorescence(mIF)assays.Kaplan-Meier curveswere used to determine treatment outcome differences according to their expression status.Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations.Results:Responders had significantly higher CD8/PD-L1(P=0.015)or CD68/PD-L1 co-expression levels(P=0.021)than non-responders in the camrelizumab plus chemotherapy group,while no difference was observed in the chemotherapy group.Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression level was associated with significantly longer PFS(P=0.002,P=0.024;respectively)and OS(P=0.006,P=0.026;respectively)than those with low co-expression in camrelizumab plus chemotherapy group.When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD-L1 co-expression stratification,significantly better PFS(P=0.003)and OS(P=0.032)were observed in high co-expression subgroups.The predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression remained statistically significant for PFS and OS when adjusting clinicopathological features.Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD-L1 or CD68/PD-L1 co-expression,the positive groups had a significantly higher proportion of TP53/KRAS co-mutations than the negative groups(both 13.0%vs.0.0%,P=0.023).Notably,enriched PI3K(P=0.012)and cell cycle pathway(P=0.021)were found in the CD8/PD-L1 co-expression group.Conclusion:Tumor immune microenvironmental marker expression,especially CD8/PD-L1 or CD68/PD-L1 co-expression,was associated with the efficacy of PD-1 blockade plus chemotherapy as first-line treatment in patients with advanced NSCLC.展开更多
文摘Advanced biliary tract cancer(BTC)and pancreatic ductal adenocarcinoma(PDAC)have poor prognoses and limited treatment options.Here,we conducted thisfirst-in-class phase II study to evaluate the efficacy and safety of SHR-1701,a bifunctional fusion protein targeting programmed death-ligand 1(PD-L1)and transforming growth factor-beta(TGF-β),combined with famitinib,a multi-targeted receptor tyrosine kinase inhibitor,in patients with advanced BTC or PDAC who failed previous standard treatment(trial registration:ChiCTR2000037927).Among 51 enrolled patients,the BTC cohort showed an objective response rate(ORR)of 28%(including 2 complete responses)and a disease control rate(DCR)of 80%,with a median progression-free survival(mPFS)of 5.1 months and a median overall survival(mOS)of 16.0 months.In the PDAC cohort,the ORR was 15%(2 complete responses),with a DCR of 60%,and the mPFS and mOS were 2.1 months and 5.3 months,respectively.Grade 3 or 4 treatment-related adverse events(TRAEs)occurred in 29.4%of patients,with no grade 5 TRAEs reported.Exploratory analyses revealed that primary tumor resection history,peripheral blood immunophenotype changes,and distinct immune-metabolic profiles were associated with treatment benefits.An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts,allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen.In conclusion,our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC,highlighting the promise of targeting PDL1,TGF-β,and angiogenesis pathways simultaneously.
基金supported by Jiangsu Hengrui Pharmaceuticals and the following grants:the National Natural Science Foundation of China(NSFC:82321003,82173128,82073377,81930065)the Natural Science Foundation of Guangdong(2021A1515012439)+2 种基金Guangdong Basic and Applied Basic Research Foundation(2024B1515020120)the CAMS Innovation Fund for Medical Sciences(CIFMS:2019-I2M-5-036)Additional funding was provided by the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0004).
文摘This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment forunresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologicallyconfirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients receivedSHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m^(2)) intravenously on day 1, along with oral capecitabine(1 g/m^(2) twice daily) on days 1-14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenancetherapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) perRECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival(PFS) was 10.3 months (95% CI: 8.3-13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% ofpatients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that hightumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactatedehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safetyprofile and potent antitumor activity in unresectable mCRC.
文摘The randomized phase 3 CHART trial(NCT03520478)revealed that rezvilutamide(REZ)plus androgen deprivation therapy(ADT)in high-volume,metastatic,hormone-sensitive prostate cancer(mHSPC)significantly enhanced radiographic progression-free and overall survival than bicalutamide(BIC)-ADT.Accordingly,we examined patient-reported outcomes(PROs)results,which were exploratory endpoints in the CHART trial.The patients were randomly allocated to receive REZ-ADT or BIC-ADT in a 1:1 ratio.The PROs were evaluated with the Brief Pain Inventory-Short Form(BPI-SF)and the Functional Assessment of Cancer Therapy-Prostate(FACT-P)questionnaires.Both study groups displayed comparable baseline pain scores and functional status.Patients administered REZ-ADT had an extended time to progression of worst pain intensity in comparison to those treated with BIC-ADT(25th percentile,9.2[95%CI 7.4-16.6]vs.6.4 months[95%CI 5.5-8.3];HR 0.75[95%CI 0.57-0.97];p=0.026).Similarly,patients received REZ-ADT exhibited a delayed time to progression of pain interference in comparison to those receiving BIC-ADT(25th percentile,20.2[95%CI 12.9-31.3]vs.10.2 months[95%CI 7.4-11.1];HR 0.70[95%CI 0.52-0.93];p=0.015).Additionally,the REZ-ADT group demonstrated a prolonged delay in the deterioration of the total score on the FACT-P questionnaire(25th percentile,12.8[95%CI 7.4-20.3]vs.6.0 months[95%CI 4.6-9.2];HR 0.66[95%CI 0.50-0.86];p=0.002),as well as most of the FACT-P subscale scores,in comparison to the BIC-ADT group.In conclusion,REZ-ADT is superior to BIC-ADT regarding the pain alleviation and enhancement of functional scales for high-volume mHSPC.
基金supported in part by grants from the National Natural Science Foundation of China(No.81871865,81874036,81972167 and 82102859)the Backbone Program of Shanghai Pulmonary Hospital(No.FKGG1802)+4 种基金Shanghai Pujiang Talent Plan(No.2019PJD048)Shanghai Science and Technology Committee Foundation(NO.19411950300)Shanghai Key disciplines of Respiratory(No.2017ZZ02012)Oncology development incentive program of Shanghai Pulmonary Hospital,Shanghai Multidisciplinary Cooperative Project for Diagnosis and Treatment of Major DiseasesKey Clinical Project Development Program of Shanghai.
文摘Background:Although programmed cell death 1(PD-1)blockade plus chemotherapy can significantly prolong the progression-free survival(PFS)and overall survival(OS)in first-line settings in patients with driver-negative advanced non-small-cell lung cancer(NSCLC),the predictive biomarkers remain undetermined.Here,we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD-1 blockade plus chemotherapy.Methods:Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone.Tumor immune microenvironmental markers,including PD-1 ligand(PDL1),CD8,CD68,CD4 and forkhead box P3,were assessed using multiplex immunofluorescence(mIF)assays.Kaplan-Meier curveswere used to determine treatment outcome differences according to their expression status.Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations.Results:Responders had significantly higher CD8/PD-L1(P=0.015)or CD68/PD-L1 co-expression levels(P=0.021)than non-responders in the camrelizumab plus chemotherapy group,while no difference was observed in the chemotherapy group.Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression level was associated with significantly longer PFS(P=0.002,P=0.024;respectively)and OS(P=0.006,P=0.026;respectively)than those with low co-expression in camrelizumab plus chemotherapy group.When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD-L1 co-expression stratification,significantly better PFS(P=0.003)and OS(P=0.032)were observed in high co-expression subgroups.The predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression remained statistically significant for PFS and OS when adjusting clinicopathological features.Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD-L1 or CD68/PD-L1 co-expression,the positive groups had a significantly higher proportion of TP53/KRAS co-mutations than the negative groups(both 13.0%vs.0.0%,P=0.023).Notably,enriched PI3K(P=0.012)and cell cycle pathway(P=0.021)were found in the CD8/PD-L1 co-expression group.Conclusion:Tumor immune microenvironmental marker expression,especially CD8/PD-L1 or CD68/PD-L1 co-expression,was associated with the efficacy of PD-1 blockade plus chemotherapy as first-line treatment in patients with advanced NSCLC.
